1. Field of the Invention
The present invention relates to the treatment of tauopathies and, more specifically, the use of mGluR5 antagonists for the treatment of tau pathologies.
2. Description of the Related Art
Indigenous residents and immigrants of the Pacific Island of Guam suffer from a high incidence of a progressive and fatal neurodegenerative tauopathy called “parkinsonism-dementia” (PD). This is a long-latency disease with phenotypic characteristics of idiopathic parkinsonism with an early-onset dementia. The disorder is found together with a second high-incidence disease, amyotrophic lateral sclerosis (ALS). The incidence of both diseases has declined dramatically over the past half century, suggesting an environmental etiology. The neuropathology of PD is hallmarked by neurofibrillary tangles (NFTs) of paired helical filaments (PHFs) composed of abnormally hyperphosphorylated forms of the microtubule-associated protein tau. The NFTs found in PD brains are ultra-structurally and biochemically similar to those in Alzheimer's disease (AD).
In contrast to AD pathology, however, studies using postmortem brains confirmed the absence of amyloid β plaques in most PD cases. Many studies have demonstrated that abnormal hyperphosphorylation and aggregation of tau are crucial to neurodegeneration in AD and tauopathies. Although the mechanism leading to the formation of NFTs is still obscure, it has been well recognized that an imbalanced regulation in protein kinases and protein phosphatases can directly cause AD-like tau hyperphosphorylation. Among the various kinases, glycogen synthase kinase-3β (GSK-3β), cyclin-dependent kinase 5, Ca2+/calmodulin-dependent protein kinase II (CaMKII), MAP kinase kinase (MEK 1/2), ERK 1/2, protein kinase A, casein kinase 1, and p70 S6 kinase have been most often implicated in tau phosphorylation.
Among the phosphatases, protein phosphatase 2A (PP2A) accounts for ˜70% of tau phosphatase activity in the human brain. PP2A is responsible for dephosphorylating most of the hyperphosphorylated sites of tau, and its activity is compromised in the AD brain. Given the increasing evidence that PD histopathologically and genetically should be classified as a tauopathy, identifying the protein kinases/phosphatases and the associated signaling cascades that regulate tau phosphorylation is of crucial importance.
Several etiological factors, especially environmental factors, genetic susceptibility, and metabolic alterations, have been proposed to contribute to PD. The nonprotein amino acid β-N-methylamino-L-alanine (BMAA) has been implicated as a potential environmental factor in PD, ALS, AD, and other neurodegenerative disorders. Although the neurotoxic effects of BMAA are not conclusive, BMAA concentrations as low as 30 μM can cause selective death of motor neurons, and a 10 μM concentration can potentiate neuronal injury induced by exposure to amyloid-β, 1-methyl-4-phenylpyridinium, or methylmercury in mixed cortical cultures. The mechanism of BMAA toxicity is complex and several fold: (i) BMAA displays agonistic properties for NMDA, AMPA/kainate, and metabotropic glutamate receptor 5 (mGluR5) and for mGluR1 receptors in a cell-specific manner, and (ii) it increases intracellular calcium levels and oxidative stress. BMAA was reported to induce learning and memory deficits accompanied by neuronal cell death in rats, although the underlying molecular mechanism by which BMAA affects tau phosphorylation and eventually toxicity has not been established.